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A Novel Inherited Mutation of SCN8A in a Korean Family with Benign Familial Infantile Epilepsy Using Diagnostic Exome Sequencing

November-December 2018

Diagnostic exome sequencing identified a novel inherited mutation (p.Gly1476Asp) in the SCN8A gene. The paper reports the case of an infant and father with this mutation who had early onset benign familial infantile epilepsy but no cognitive impairment.

Chemical–genetic attenuation of focal neocortical seizures

May 27, 2014

One of the commonly known pharmacoresistant epilepsy types is focal epilepsy, and many patients have no effective treatment options. In this paper, a chemical-genetic approach was taken to achieve localized suppression of neuronal excitability using viral expression in rats.

Loss-of-function variants of SCN8A in intellectual disability without seizure

August 2017

Two SCN8A missense mutations (p.Gly964Arg and p.Glu1218Lys) were examined in this paper that present with intellectual disability and developmental delay but no seizures. Both these mutations completely prevented the generation of sodium currents within transfected cell lines. These observations extend the established phenotypic spectrum of SCN8A.

De novo variants in the alternative exon 5 of SCN8A cause epileptic encephalopathy

October 2nd, 2017

Exome sequence data from 54 epilepsy patients and their unaffected parents to help identify the molecular diagnoses that were not initially provided. In the 54 trios, two de novo missense variants in SCN8A in the alternative exon 5A. This helps expand the range of SCN8A variants in epileptic encephalopathy.

High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

November 2nd, 2017

The cause of developmental and epileptic encephalopathies is unknown in a majority of cases. The authors performed whole-genome sequencing in 197 individuals and performed meta-analysis to document de novo mutations in certain candidate genes.

It has been shown that cannabidiol (CBD) can alleviate certain epilepsies, however its pharmacological profile is unknown. The authors tested whether the anticonvulsant effects of CBD would be prevented by cannabinoid and vanilloid receptor blockers to help determine its pharmacological profile.

Early-onset epileptic encephalopathy with de novo SCN8A mutation

October 28th, 2017

In this case study, a de novo mutation was reported in an EOEE patient who died from SUDEP. The data found help strengthen the association between SCN8A and EOEE and urge the screening for this mutation for early prevention of SUDEP.

Impaired bone and muscle development in young people treated with antiepileptic drugs

September 7th, 2017

A case-controlled study of patients ranging from 5-18 years old was completed to investigate the effects of antiepileptic drugs on bone development in young people. Researchers found that that those taking antiepileptic drugs had an increased prevalence of fractures, with the distal radius being the most common fracture site in this study.

Effects of the N1768D mutation on the neurons within the medial entorhinal cortex (mEC) were studied in this paper. mEC neurons are known to provide excitatory input to the dentate gyrus and hippocampus and are known to elevate the circuit excitability in animal models with temporal lobe epilepsy. It was found that unlike hippocampal or neocortical neurons, the mEC neurons are hyperexcitable and this increase in excitability precedes the onset of seizures by more than one month.

The ketogenic diet has shown to be successful in reducing seizures in pharmaco-resistant epilepsy patients, however it is highly unpalatable and difficult to follow. A new diet which combines medium-chain fatty acids, polyunsaturated fatty acid, low glycemic index carbohydrates, and a high BCAA/AAA ratio has shown to reduce excitatory drive and produce results similar to the ketogenic diet.

While it is unknown whether SCN8A mutations can lead to skeletal complications, there have been reports of children with SCN8A mutations who also suffer from skeletal fractures. Researchers analyzed skeletal phenotypes of 2-week-old SCN8A-null mice and revealed there was reduced bone mass as compared to control littermates.

A retrospective study was conducted in five Israeli pediatric clinics examining the effect of cannabidiol (CBD) on children with intractable epilepsy. The results showed that CBD had a positive effect on seizure load and also was associated with improvements in behavior, language, communication, motor skills, and sleep. Some adverse events were also reported which included drowsiness, fatigue, gastrointestinal disturbances and irritability. Further clinical trials using CBD are warranted to validate these findings.

Carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy

April 7th, 2017

Carbamazapine and oxcarbazepine are some of the common choices for the treatment of focal epilepsy. One of the common side-effects from using these drugs is hyponatremia (low sodium levels in the blood). This study collected sodium blood levels of adults taking these drugs and looked at the prevalence for hyponatremia within this cohort.

Advances in epilepsy gene discovery and implications for epilepsy diagnosis and treatment

February 15th, 2017

This article outlines recent findings in a variety of genetic mutations related to epilepsy, including SCN8A. It summarizes how precision medicine and gene discovery are facilitating rapid progress in the classification of epilepsy, as well as development of medications targeted toward patients with these specific genetic mutations.

Neuronal hyperexcitability in a mouse model of SCN8A epileptic encephalopathy

February 13th, 2017

Recent experimentation through mouse models suggests that a N1768D mutation in SCN8A results in hyperexcitability and an elevated persistent sodium current in hippocampal neurons. This data suggests that SCN8A plays a role in neural excitability, which could explain the mechanism through which early infantile epileptic encephalopathy (EIEE) causes severe seizures and cognitive impairment.

De novo mutations in the SCN8A gene are at an increased risk for sudden unexpected death in epilepsy (SUDEP). In this study, the cardiac phenotype of a mouse model expressing the p.Asn1768Asp mutation in Scn8a was investigated for alterations in cardiac excitability. The authors observed prolongation of the early stages of action potential repolarization in mutated myocytes.

Detection of Fetal Seizures Guides Approach to Diagnosis and Treatment

October 10th, 2016

This paper describes the first reported case of a SCN8A mutation (p.Ile240Val) with clinical prenatal-onset seizures. Ultrasonography was found to be useful for identifying fetal seizures which may be treatable in utero. Finally the authors report that the clinical approach to fetal seizures should involve a multidisciplinary team.

SCN8A-Related Epilepsy with Encephalopathy

August 25th, 2016

A summary of the clinical characteristics of SCN8A-related epilepsy. This complete review covers everything from available testing and diagnostic procedures available for SCN8A-related epilepsy, to the management of symptoms, in order to serve as a point-of-care resource for clinicians.

In a recent study it was shown that high doses of phenytoin were effective in four patients with SCN8A encephalopathy. Researchers have created a cell line with a SCN8A mutation (p.Ile1327Val) to study the cell's response to phenytoin.

How Antiepileptic Drugs (AEDs) May Relate to Fracture Risk

June 21st, 2016

IFracture risk is a serious comorbidity in epilepsy and may relate to the use of antiepileptic drugs (AEDs). Many AEDs inhibit ion channel function, and the expression of these channels in osteoblasts raises the question of whether altered bone signaling increases bone fragility. This study aimed to confirm the expression of voltage-gated sodium (NaV) channels in mouse osteoblasts, and to investigate the action of carbamazepine and phenytoin on NaV channels.

SCN8A mutation in a child presenting with seizures and developmental delays

November 1st, 2016

Researchers identified a de novo missense SCN8A mutation (p.Leu267Ser, c.800T>C) in a 4 year old female. This case report provides information on the child's clinical presentation,family history, and genetic analysis.

2015 - This is What You Need to Know About SCN8A

August 31st, 2015

In 2015, SCN8A has emerged as an important gene in epileptic encephalopathy. SCN8A encodes the voltage-gated sodium channel alpha subunit Nav1.6, and was first implicated in epileptic encephalopathy in 2012. Since then, approximately 100 cases of early-infantile...

SCN8A Encephalopathy - How it differs from Dravet Syndrome

January 13th, 2015

For some reason, SCN8A always met some resistance. In contrast to other epilepsy genes, it took a while for the community to embrace this gene as a genuine cause of epileptic encephalopathies. A recent publication in Neurology now investigates the phenotypic spectrum of SCN8A encephalopathy – and points out important features that distinguish this condition from Dravet Syndrome.

Genome Sequencing Finds Unknown Cause Epilepsy

Only 10 years ago, deciphering the genetic information from one individual in a matter of weeks to find a certain disease-causing genetic mutation would have been written off as science fiction.

It was the time of the Human Genome Project, and it had taken armies of sequencing robots working around the clock for almost a decade to unravel the complete sequence of the human genetic code – referred to as the genome

Neurotransmitters and Sodium Channelopathies; Possible Link?

Beyond seizures — the importance of comorbidities in epilepsy

August 17th, 2017

The exact prevalence of comorbidities in pediatric patients is somewhat unknown at this time as comorbidities can be under-diagnosed. This News & Views article provides insight on the importance of early identification and treatment of comorbidities with children with epilepsy.

Regulation of Thalamic and Cortical Network Synchrony by SCN8A

February 23rd, 2017

This article outlines the mechanisms through which a mutation in SCN8A results in seizures. Through experimentation in mouse models, researchers have found that decreased SCN8A function in the cortex can lead to convulsive seizure resistance, while decreased SCN8A function in the thalamus can generate absence seizures. The results of this study could motivate future research on the role of SCN8A in other thalamic processes including sleep, attention, and consciousness.

Progress in Epilepsy: Latest Waves of Discovery

February 22th, 2017

This article summarizes advancements in biotechnology and recent discoveries in epilepsy, which will prospectively be translated into distinct therapy options for the individual patient. These discoveries include the role of inflammatory cell types in the development of epilepsy, the use of intracranial neurostimulation in interrupting seizures, as well as a discussion of the role of bioinformatics in gene identification.